Failure to supply energy to match the body's demands limits the functional reserve capacity, and under certain periods of stress, such as ischemia, can lead to irreversible cell and tissue damage. This matching is critical in tissues with high and rapidly fluctuating metabolic rates such as the heart. Mitochondria are the main ATP suppliers to meet cellular demands. The fuel used by mitochondria is transported across the inner mitochondrial membrane to the matrix and produces a source of electrons whose redox-potential energy is, in turn, harnessed by the electron transport chain. The flux of electrons is reflected in oxygen consumption. The energy released from this electron flow is used to transport protons out of the matrix across the inner mitochondrial membrane forming a gradient whose proton-motive force drives ATP synthase to make ATP. This upstream regulation is known as the push mechanism. A complete description of the ATP synthase control mechanisms is still lacking. We discovered that mammalian ATP synthase, previously believed to be a machine running exclusively on H+, actually utilizes almost 4 K+ for every H+ to make ATP inside intact cellular mitochondria. Thus, ATP synthase is, for the first time, identified as a primary mitochondrial K+ uniporter, i.e., the primary way for K+ to enter mitochondria; furthermore, since this K+ entry is directly proportional to ATP synthesis and regulates matrix volume, this in turn serves the function of directing the matching of cellular energy utilization with its production. For the first time, we show that the chemo-mechanical efficiency of ATP synthase can be up-regulated, and that this occurs by certain members of the Bcl-2 family and by certain K+ channel openers acting via an intrinsic regulatory factor of ATP synthase, IF1, which we identified as itself a novel and previously unrecognized member of the Bcl-2 protein family. As a consequence of the foregoing, we discovered that ATP synthase is also a recruitable mitochondrial ATP-dependent K+ channel which serves critical functions in cell protection signaling that can limit the damage of ischemia-reperfusion injury. Thus, we discovered the molecular identity of two mitochondrial potassium channels, an entirely new function set for ATP synthase, and what is likely the primary mechanism by which mitochondrial function matches energy supply with demand for all cells in the body. We discovered that IF1 is a novel, highly conserved BH3-only member of the Bcl-2 protein family displaying, in addition to the BH3 linear sequence motif, a functional BH3-domain-like molecular recognition feature (MoRF) which enables the modulation of ATP synthase function. The phylogenetic tree shows that IF1s linear motif is most closely related to the BH3-only proteins (e.g. Bak, Bid, etc.). These findings will fundamentally change our understanding of the regulation of mitochondrial energy production and homeostasis. Because we now know the identity of the mitochondrial K+-uniporter to be the ATP synthase, and given its dominant permeation by K+ over H+ to make the daily equivalent of the body's weight in ATP, the actual rate and volume of mitochondrial K+ flux cycling is huge (and not the previously believed trickle-leak). To assess directly and quantitatively these predictions based on proteoliposome-reconstituted ATP synthase, and to extend these observations to the organelle level, we investigated the bioenergetic performance (respiration and P/O ratio) in the absence or presence of K+ in isolated rat heart mitochondria at constant (physiological) osmolality. Employing radioactive tracers, we measured volume, and the individual components of the protonmotive force (PMF), mitochondrial membrane potential and delta-pH, in the absence or presence of K+ under states 4 and 3 respiration. Together, the data indicate that mitochondria synthesize 3-fold higher amounts of ATP (at 1.6-fold faster rates, and a K+/H+ stoichiometry of almost 3) in the presence of K+ as compared to conditions in which this cation is absent. These results are fully consistent with predictions arising from experiments performed with purified ATP synthase reconstituted in proteoliposomes or lipid bilayers.